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This diagnostic study describes the development of an assay for human papillomavirus–driven cancers of the oropharynx and the role viral integration could play in the process.

Neuroendocrine neoplasms are uncommon in the cervix with almost all representing neuroendocrine carcinomas (NECs), either small cell or large cell type. Cervical low-grade neuroendocrine tumors (NETs) are extremely rare with few recent reports using contemporary modern diagnostic criteria. We report 3 cases of cervical NET in patients aged 32 to 57 yr and undertake a review of the literature. The first case was a pure grade 2 NET with pelvic lymph node metastasis (FIGO stage IIIC1). In the second case, a grade 1 NET was associated with high-grade squamous intraepithelial lesion, adenocarcinoma in situ and human papillomavirus (HPV)-associated adenocarcinoma and was FIGO stage IA1. The third patient underwent chemoradiotherapy following a biopsy diagnosis of a high-grade NEC which was radiologically FIGO stage IIIC1 and salvage hysterectomy revealed residual tumor with features of a grade 1 NET. In all cases, the NET was diffusely positive with at least 2 of the neuroendocrine markers chromogranin, synaptophysin, and CD56. The first tumor was p16 negative and the third exhibited block-type immunoreactivity. Molecular tests revealed high risk HPV types 18 and 51 in the third case but no HPV in the first case. p16 immunohistochemistry and HPV molecular testing was not available in the second case. The patients remain disease free with follow-up ranging from 2 to 8 yr. Since a combination of NET and NEC is extremely rare at all sites due to a different pathogenesis, we speculate that in the third case, the NET developed out of the NEC as a "maturation" phenomenon secondary to chemoradiotherapy.

The aim of this study was to ascertain the safety of high-intensity focused ultrasound (HIFU) for high-grade cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) in patients with fertility requirements. This was a prospective one-arm study. Consecutive CIN 2/3 patients diagnosed with histopathology were screened, enrolled and treated from September 2019 to September 2020 in the Affiliated Hospital of North Sichuan Medical College. All patients were treated with a combination of HIFU and antiviral treatment with REBACIN. The scheduled follow-up visits were 1 week, 1 mo, 3 mo, 6 mo and 12 mo after surgery. The primary outcomes included cure and human papillomavirus clearance rates. We screened 287 consecutive CIN 2/3 patients in our hospital, 29 of whom were enrolled and treated in this study. The cure rate reached 82.8% at 7 mo after treatment and 96.6% within 1 y. The HPV-negative rate reached 72.4% (21/29) around 6 mo after treatment, with mild side effects during and after the procedure. Our study suggests that in CIN 2/3 study participants with fertility requirements, HIFU + REBACIN therapy is a safe and effective therapeutic option with a high cure rate, HPV clearance and few side effects.

Rapid human papillomavirus (HPV) screening is urgently needed for preventing and early diagnosis of cervical cancer in rural areas. To date, no HPV nucleic acid test (NAT) can be implemented within a single patient visit starting from clinical samples. Here, we develop a hydrogel loop-mediated isothermal amplification (LAMP) method in a fashion of large-scale parallel (about 1000 cells) in situ HPV DNA detection in clinical cervical exfoliated cells at the single-cell level. It can be used with a hotplate and smartphone to obtain HPV NAT results in less than 30 min, which is especially suitable for the on-site scenario. We apply this rapid HPV NAT on 40 clinical cervical exfoliated cell samples and compare the results to a clinical gold standard quantitative polymerase chain reaction (qPCR) method [area under curve (AUC), 1.00]. Meanwhile, our assay can provide HPV infection information for large-scale parallel single clinical cervical exfoliated cells, which cannot be received from traditional NAT methods. Our findings suggest the potential of in situ hydrogel LAMP as a powerful tool for clinical HPV screening and fundamental research.

Persistent infection with high-risk (HR) Human Papilloma Virus (HPV) genotypes has been shown to play a significant role in the development of cervical intraepithelial neoplasia (CIN) and CC (cervical cancer). The present study aimed to determine the distribution and quantification of viral load of HPV genotypes in numerous genital samples obtained from women undergoing routine gynaecological care in different regions of Turkey.HPV typing was done by HPV QUANT-21 Quantitative RT-PCR Kit®, which is intended for the specific identification and quantification of low-risk (HPV 6, 11, 44) and high-risk (HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) from female subjects in Turkey.From the total of 5975 samples, 2777 were positive for at least one HPV genotype, with an overall frequency of 46.4%. 1695 patients were positive for only one or more LR-HPV genotypes (61%) and 812 patients were positive for one or more HR-HPV genotypes (29%). The frequency of LR-HPV genotypes was 31.4%, while the frequency of HR-HPV genotypes was 118.8%. Our tecnology had a positive advantage to calculate the concentration of each genotypes. Although genotype 52 ranked fifth in frequency, it showed the highest mean concentration, with a value of 5.38 log (copies/sample).The presence and genotype of viruses before HPV vaccination have also gained importance. The data obtained would provide guidance for prevention strategies, mainly of vaccination. We decided to add a new estimate to the effectiveness of currently available HPV vaccines and the development of screening programs to prevent and decrease the incidence of CC in Turkey. Further studies would be planned to measure and define the high infection level that can lead to the development of cervical neoplasia. Using this tecnology could give us a clinical desicion to degree the cytological changes.

Replacing cisplatin with cetuximab concurrently during radiotherapy has been one of the strategies of treatment de-escalation in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, until recently, there were limited data on the efficacy and safety of such an approach. A systematic search of the literature was carried out to identify prospective randomised controlled trials comparing definitive cisplatin-based chemoradiotherapy (CT-RT) versus cetuximab-based bioradiotherapy (BRT) in HPV-positive OPSCC. Overall survival and locoregional control were primary outcomes of interest; rates of acute and late toxicities (≥grade 3) were secondary end points. Outcome data were aggregated using a random-effects model as per Cochrane methodology including risk of bias assessment and expressed as hazard ratio or risk ratio as appropriate with respective 95% confidence intervals. Data from five randomised controlled trials involving 1560 patients with HPV-positive OPSCC were aggregated in the meta-analysis. Cetuximab-based BRT was associated with a significantly increased risk of death (hazard ratio = 2.83, 95% confidence interval 1.22-6.57; P = 0.02) and locoregional relapse (hazard ratio = 2.78, 95% confidence interval 1.77-4.39; P0.0001) compared with cisplatin-based CT-RT. Cisplatin was associated with higher rates of acute ≥grade 3 toxicity in terms of acute kidney injury, dry mouth, febrile neutropenia, hearing impairment, nausea and vomiting, whereas dermatitis and acneiform rash were more common with cetuximab. There were no significant differences in overall rates of late ≥grade 3 toxicity (risk ratio = 0.63, 95% confidence interval = 0.36-1.10; P = 0.10). In conclusion, there is moderate-certainty evidence that cetuximab-based BRT leads to inferior efficacy outcomes compared with cisplatin-based CT-RT in the definitive curative-intent management of HPV-associated OPSCC.

This study aimed to investigate the distribution of human papillomavirus 16 (HPV16) variants that contribute to the development of HPV-related oropharyngeal carcinoma (HPV-OPC) in the Japanese population and to evaluate genetic variations in the sequence encoding the L1 antigen region of the viral outer shell that is targeted by existing vaccines and is relevant for designing a prevention strategy to combat the exponential increase in HPV-OPC cases in Japan.Seventy Japanese HPV-OPC patients treated at Tohoku University Hospital were included in the study. DNA was extracted from formalin-fixed, paraffin-embedded tissue samples. Polymerase chain reaction and direct nucleotide sequencing were performed to determine the nucleotide polymorphisms necessary for the classification of HPV16 variants and to assess genetic diversity in the HPV16 L1 antigen region, including the BC, DE, EF, FG, and HI loops.The most common variant of HPV16 was the A4 sublineage (88.6%), conventionally called the Asian type, followed by the A1/2/3 (10.0%) sublineage, classified as the European type. The only nonsynonymous substitution detected in the L1 antigen loop region was p.N181T in the EF loop, which was found in 28/70 (40%) cases. In contrast, no nonsynonymous substitutions were observed in the DE, FG, and HI loops, which are particularly important regions in the antigen loop targeted by existing HPV vaccines.The most common HPV16 variant in Japanese HPV-OPC patients was the A4 subtype. The L1 antigen region is highly conserved, suggesting sufficient efficacy of existing HPV vaccines. These findings provide important information that will aid in the design of an HPV16 infection control strategy using existing HPV vaccines to prevent the spread of HPV-OPC in Japan.

Mongolia is a sparsely populated country; however, almost fifty percent of the population lives in the capital city. Medical care services and exceptionally well-organized cervical cancer screening tests are limited in remote areas. To improve cervical cancer screening test coverage, we compared the interest between physicians taking samples and self-sampling among the attendees in this study.A total of 175 women participated in this study. The hundred twelve women visited the Gynecology ward, and the sixty-three women were provided with the cervical self-sampling test kit and filled out a questionnaire. Subsequently, the acceptability of physician taking and self-sampling were evaluated using a questionnaire. All specimens were processed using the TACAS LBC system, and the quality of samples was tested by cytology.Regarding the acceptability of self-sampling, the selections for subsequent screening were 36% self-sampling and 64% gynecologist-sampling methods. The acceptability rates were higher in the remote areas than the urban areas. However, 64% of the participants lacked knowledge that the causative agent of cervical cancer is the human papillomavirus, and 66.9% mainly were sexually transmitted. In addition, 82.3% of the women surveyed were unaware that there was a vaccine to prevent cervical cancer, but 88.6% wanted to be vaccinated. Of most women, 44.4% chose self-sampling due to no embarrassment in the gynecological examination. The self-sampling preferences were dominant in the old age group (61.6%). The cytology satisfaction rate in physician-sampling (99.1%) was higher than in the self-sampling group (69.8%).The Implementation of the self-sampling tool may be considered a primary screening. The self-sampling test can adopt into the early screening program and may increase the coverage of the screening program and improve the quality.

Introduction Head and neck cancer appears to be increasing in incidence, with potential changes in aetiology proposed. This paper aims to provide a narrative overview of the epidemiological literature to describe the disease burden and trends in terms of incidence and mortality both in the UK and globally and to review the evidence on current risk factors.Methods A search was performed on multiple databases (PubMed and Epistemonikos), applying filters to identify systematic reviews and meta-analyses which investigated head and neck cancer incidence, mortality and risk factors. International and UK cancer registries and sources were searched for incidence and mortality data.Results Multiple definitions of head and neck cancer are employed in epidemiology. Globally, incidence rates have increased in recent decades, largely driven by oropharyngeal cancer. Mortality rates over the last decade have also started to rise, reflecting the disease incidence and static survival rates. Major risk factors include tobacco smoking alone and in combination with alcohol consumption, betel chewing (particularly in Southeast Asian populations) and the human papillomavirus in oropharyngeal cancer.Conclusions These epidemiological data can inform clinical and preventive service planning for head and neck cancer.

Human papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent).1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20-26, 27-35, or 36-45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference -10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio 0.5.Among the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded -10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths.This study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.

The female reproductive tract, similar to other mucosal sites, harbors a specific microbiome commonly dominated by Lactobacillus species (spp.), which has an essential role in maintaining health and homeostasis. Increasing evidence shows that genital tract dysbiosis and/or specific bacteria and cytokines might have an active role in the development and/or progression of HPV infection and cervical intra-epithelial neoplasia (CIN) and as a result cervical cancer. Cross-sectional and longitudinal studies reported that Lactobacillus spp. depletion increases with severity of CIN and that this may negatively affect disease regression rates. It is plausible that Lactobacillus deplete microbiome composition may lead to a pro-inflammatory environment that can increase malignant cell proliferation and HPV E6 and E7 oncogene expression. Future longitudinal cohorts and mechanistic experiments on HPV transfected cells models will further permit exploration of the impact of Lactobacillus spp. on HPV infection.

Select protease inhibitors (PI) have been found to be effective in decreasing human papillomavirus oncoprotein expression. This study evaluated whether the topical PI, Saquinavir (SQV), promotes viral clearance in an infectious mouse model with Mus musculus papillomavirus 1 (MmuPV1). NOD scid gamma (NSG) mice were anally infected with ∼4 × 10sup8/supviral genome equivalents of MmuPV1 and 120 days post-infection (when majority have high-grade anal dysplasia), began topical treatments: control (mock), 7,12-dimethylbenz(a)anthracene (DMBA) only, once weekly to promote carcinogenesis, 1% SQV only, daily (Monday - Friday), and SQV + DMBA. Viral MmuPV1 load was analyzed from anal lavages pre and post-treatment. Anal tissue was harvested, processed, and evaluated for drug absorption, grade of anal disease, and anal viral RNA. Results suggest that topical SQV promotes decreased viral shedding in female mice treated with SQV.

This study aimed to investigate the prevalence characteristics of human papillomavirus (HPV) infections in 29,508 female cases in Jinshan District, Shanghai.The current research represents a retrospective study that included 29,508 women who received cervical screening in the Jinshan Branch of Shanghai Sixth People's Hospital from 2010 to 2020. The overall prevalence, distribution types, age-specific prevalence and annual trends were analysed.The overall HPV infection rate among the patients was 21.97%. They were primarily high-risk HPV (HR-HPV) infections (20.30%) and single HPV infections (15.91%). A general decline in HPV and HR-HPV prevalence was observed with time from 33.52% to 25.45% in 2011 to 21.47% and 20.18% in 2020. The most common HPV genotypes were HPV52, HPV16, HPV58, HPV51, HPV53 and HPV68. The infection rates of HPV genotypes, including HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV42, HPV43, HPV66 and HPV68, showed overall declines across different years. The age-specific prevalence of total HPV and HR-HPV infections formed an approximate U-shaped curve with two peaks, one in the ≥55 age group (29.75%, 28.43%) and the other in the25 age group (22.93%, 20.85%). Both total HPV and HR-HPV infection rates decreased to their lowest in the 25-34-year age groups.The prevalence of HPV infections showed a downward tendency with time. Single HPV genotype infections and HR-HPV infections were predominantly detected. The after prevalent characteristics of HPV can help to guide HPV vaccinations and cervical cancer screenings: 1) non-HPV16/HPV18 H R-HPV genotypes were prevalent; 2) non-vaccine-covered HPV53, HPV51 and HPV68 were also prevalent; 3) women above the age of 55 years had the highest HPV and HR-HPV infection rates.

To characterize HPV genotype distribution in HSIL and ICC- biopsies, of WLWH, in Europe, as compared to HIV-negative women.Cohort- and nested -case control study.We characterized HPV genotype distribution by performing PCR on HSIL and ICC biopsies from WLWH (n = 170); 85 cases were compared to 85 HIV-negative matched controls. The proportion of patients that might be protected by HPV vaccines was estimated.Among WLWH (median age 36 years-old, median duration of HIV infection 70,5 months, 79% under cART): the most frequently detected HPV were HPV16 (30%), HPV35 (16%), HPV58 (14,7%), HPV31 (13,5%), and HPV52 (11,7%). HPV16 was less frequently found in WLWH, originating from Central Africa (20,5%) compared to other African regions (35,5%) (p = 0,05) or world regions (38,8%) (p = 0,007). Multiple versus single high-risk HPV infections were associated with younger age (≤35 years)(odds ratio (OR) 2,65 (95%IC: 1,3-5,2,p = 0,002), lymphocyte CD4 count 350 cells / µL (OR 2,7 (95%IC: 2-8,5; p = 0,005), use of cART for 18 month OR 2,2 (95%IC: 1,1-4,5),p = 0,04) or a cumulative time with undetectable HIV viral load of less than 12 months (OR 4,2 (95%IC: 2-8.5,p = 0,001). HPV 31, 33 and 35 were more frequently detected in samples from WLWH than in HIV-negative controls (p 0,05). The 9-valent vaccine would increase HPV protection, in HIV-positive and negative women (p 0,001).WLWH are more frequently infected with high-risk HPV other than 16 and 18 than HIV-negative ones. The use of 9-valent vaccine may prevent HSIL or ICC in up to 85% of the women. Adding HPV 35 to the HPV vaccine panel, might improve vaccine effectiveness in WLWH.

To assess the efficacy and safety of focused ultrasound (FU) for high-risk human papillomavirus (HR-HPV) infection-related cervical low-grade squamous intraepithelial lesions (LSIL).Of 185 patients who met the inclusion criteria for this prospective study from October 2020 to November 2021, 95 received FU and 90 were followed up only. At the six-month follow-up, the HR-HPV clearance and LSIL regression rates of the groups were compared and factors affecting HR-HPV clearance were analyzed. The safety and side effects of FU were evaluated.No significant difference was found in the baseline clinical data between the two groups (For patients with HR-HPV infection-related histological LSIL, FU can eliminate HR-HPV infection and cause lesions to regress in a short time, with few adverse effects and good tolerance.

BACKGROUND: Human papillomavirus-associated oropharynx squamous cell carcinoma (HPV-OPSCC) has no known pre-malignant lesion. While vaccination offers future primary prevention, there is current interest in secondary prevention. The feasibility of clinical evaluation of individuals at increased risk for HPV-OPSCC is unclear. METHODS: Individuals with risk factors for HPV-OPSCC were enrolled in a prospective study (MOUTH). Participants positive for biomarkers associated with HPV-OPSCC were eligible for a clinical evaluation which comprised a head and neck examination and imaging with ultrasound and/or magnetic resonance imaging (MRI). This study was designed to evaluate feasibility of clinical evaluation in a screening study. RESULTS: 384 participants were eligible for clinical evaluation. Of the 384, 204 (53%) completed a head and neck examination or imaging. Of these, 66 (32%) completed MRI (n=51) and/or ultrasound (n=64) studies. CONCLUSIONS: Clinical evaluations, including head and neck examination and imaging, are feasible in the context of a screening study for HPV-OPSCC.

To compare the efficacy and safety of focused ultrasound (FUS) therapy and cryotherapy for cervical squamous intraepithelial lesion (SIL).In this retrospective study, data pertaining to women treated for cervical SIL with FUS therapy or cryotherapy at the Second Affiliated Hospital of Chongqing Medical University between 21 April 2018 and 31 August 2020 were obtained. The patients were followed up after 3-6 and 6-12 months. The proportions of women with no evidence of disease, recurrent disease, clearance of the human papillomavirus (HPV) and adverse effects or complications were determined.Of the 250 women with complete data who were included in the study, 144 and 106 received FUS therapy and cryotherapy, respectively. Overall, FUS therapy was observed to be more effective than cryotherapy (91.7 vs. 79.2%,The results of this study suggest that FUS therapy is superior to cryotherapy in the treatment of cervical LSIL.

Anal squamous cell carcinoma (SCC) is a human papillomavirus (HPV)-mediated malignancy with increasing incidence. Human immunodeficiency virus (HIV) infection is a significant risk factor for anal SCC; however, it is unknown if HIV infection alters anal lesion progression and HPV strain profile. This study aims to determine whether HIV coinfection is associated with progression of HPV-mediated anal lesions and on their HPV strain diversity. This is a retrospective cohort study of adults with anal squamous intraepithelial lesion (SIL) who presented for anorectal sampling between 2010 and 2019. Using the full cohort, we performed clinicopathologic epidemiologic analysis of HIV coinfection on lesion progression. Using a subset of patients, we conducted molecular analysis of HPV strain diversity as related to HIV status and progression. Our cohort included 2203 individuals, of which 940 (43%) were HIV+. HIV+ status was associated with faster progression at all levels of dysplasia. Our molecular cohort included 329 adults, of which 190 (57.8%) were HIV+. HIV+ status was associated with higher HPV strain diversity (median: 7 [5-9] versus median: 4 [4-6], P .001). Latent class analysis identified specific HPV strain signatures associated with progression. We demonstrate that HIV+ individuals had faster rates of anal SIL progression and that almost all HPV strains were more prevalent in anal samples from HIV+ adults. Our results imply that HIV

Cervical cancer screening can effectively reduce new cervical cancer cases, including in Thailand. The abnormal results are subsequently referred for colposcopy. To avoid unnecessary colposcopy, an efficient triage is still needed for validation. This study aimed to investigate the overall positivity of cytology-based screening, HPV detection, and p16/Ki-67 dual staining and evaluate different triage strategies for predictive diagnosis of abnormal cervical lesions in northeastern Thailand.Cervical cells were collected from 191 women who came for cervical screening in the gynecological outpatient department during March 2019-February 2020. Pap smear samples were classified into 6 groups including 17 atypical glandular cells (AGC), 21 atypical squamous cells of undetermined significance (ASC-US), 7 atypical squamous cells - cannot exclude HSIL (ASC-H), 26 low-grade squamous intraepithelial lesions (LSILs), 19 high-grade SILs (HSILs) and 101 no squamous intraepithelial lesion (noSIL). Polymerase chain reaction (PCR) was performed for HPV DNA detection. HPV genotyping was determined by reverse line blot hybridization. P16/Ki-67 dual staining was performed by using CINtec PLUS Cytology kit. Biopsies from abnormal screening were collected for surgical pathology classification.High-risk HPV (HR-HPV) infection was 2.97%, 29.41%, 38.10%, 57.14%, 46.15% and 84.21% in noSIL, AGC, ASC-US, ASC-H, LSIL and HSIL cytology respectively. P16/ Ki-67 in noSIL, AGC, ASC-US, ASC-H, LSIL and HSIL was 0.99%, 5.88%, 9.52%, 42.86%, 26.92% and 63.16%, respectively (P-value0.001). Among p16/Ki-67 positive cases, 96.15% (25/26) were infected with HPV and 84.62% (22/26) were HR-HPV. The overall positivity of each and co-testing between cytology or HPV DNA testing or p16/Ki-67 dual staining was evaluated. In each cervical lesion, primary HPV DNA testing showed the highest sensitivity, but low specificity. The combined all HPV/HR-HPV with p16/Ki-67 detection increased the specificity of abnormal cervical lesions.P16/Ki-67 dual stain cytology in HPV-positive women performs well for diagnosis of abnormal cervical lesions and should be considered for management of HPV-positive women to avoid unnecessary colposcopy referrals.

This study was to determine the prevalence of HPV in non-vaccinated women from East China, and the association between prestored smartphone monitored physical activity and the risk of human papillomaviruses (HPV) infection and cervical cancer.We retrospectively reviewed medical records of unvaccinated women received first-time cervical HPV screening in the Affiliated Cancer Hospital of University of Chinese Academy of Sciences between March 2018 and December 2019. HPV genotyping was examined by the GenoArray. Physical activity defined by any movements at speeds of 0.5-2 m/s was obtained from smartphones. We collected prestored physical activity data for 6 months prior to the HPV screening. Logistic regression models were applied to determine the association between physical activity and the risk of HPV infection and cervical cancer.A total of 11,730 women were initially included. Women with cervical cancer had significantly higher prevalence of infection with any high-risk (HR) HPV, or with individual HPV16, 18, 31, 33, 45, 52 and 58. Among them, 896 controls and 289 cervical cancer women had information of smartphone monitored physical activity. Multivariate logistic regression analysis showed that more daily physical activity time (or distance) was a protective factor for infection with any HR HPV, or infection with HPV16, but not other individual HPVs. Increased age, less physical activity time (or distance), and infection with any HR HPV (16, 18, 31, 52 and 58) were associated with a significantly increased risk of cervical cancer. In contrast, obesity was not associated with risk of HPV infection and cervical cancer.The high prevalence of HPV infection in unvaccinated women highlights the importance of prevention. More daily physical activity time (or distance) may help to reduce the risk of HPV infection and cervical cancer. Smartphone monitoring is an effective tool for recording physical activity.br /.

Cervical adenocarcinoma (CAC) comprises a heterogeneous group of tumors that are not universally associated with HPV infection. As has been shown in other organs, it is becoming increasingly apparent that HPV status significantly affects the prognosis of adenocarcinoma. We conducted a systematic review and meta-analysis to investigate the infection status of high-risk Human papillomavirus (hrHPV) in CAC and evaluate its impact on the survival of patients.PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials.gov were searched from inception to May 1st, 2022. Data on HPV infection status and survival outcomes were evaluated using STATA 16.0.Seventy-one studies with 11,278 participants were included in HPV infection analysis and eight studies with 1099 participants were included in prognosis analysis. The HPV infection rate (including high-risk and low-risk) and hrHPV infection rate in CAC were 75% (95% CI 0.70-0.80, 6978 participants) and 75% (95% CI 0.70-0.81, 4906 participants), respectively. HPV-16 and -18 were the most common HPVs in CAC, with pooled infection rates of 37% (95% CI 0.33-0.41, 7848 participants) and 34% (95% CI 0.30-0.38, 7730 participants), respectively. hrHPV infection was associated with better overall survival (HR 0.23, 95% CI 0.11-0.47, 1013 participants), better disease-free survival (HR 0.18, 95% CI 0.07-0.43, 292 participants), better progression-free survival (HR 0.20, 95% CI 0.08-0.47, 271 participants) and less recurrence (RR 0.30, 95% CI 0.07-0.43, 181 participants).HPV infection rates were high in CAC. HPV-16 and -18 had the highest infection rates in CAC. However, hrHPV infection was associated with better survival and less recurrence. Future studies should clarify the relationship between hrHPV infection and other prognostic factors and make reasonable treatment strategies for CAC with different HPV status.CRD42022319390.

To determine the baseline and cumulative risks of cervical intraepithelial lesion grade 3 (CIN3) and invasive cervical cancer in patients withlt;CIN2 colposcopy findings after a low-grade screening cytology finding (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion [LSIL]).By linking administrative databases, including cytology, pathology, cancer registries, and physician billing history, a population-based cohort study was performed on participants withlt;CIN2 initial colposcopy results after a low-grade antecedent cytology finding, between January 2012 and December 2013. Three and 5-year risks of CIN3 and invasive cervical cancer were generated using Kaplan-Meier survival analysis.Among the 36 887 participants included in the study, CIN3 incidence based on referral cytology were as follows at 3 and 5 years, respectively: normal, 0.7% and 0.9%; ASCUS, 4.31% and 5.6%; and LSIL, 5.9% and 7.2%. Three- and 5-year incidence of invasive cancer were 0% and 0.02% for normal cytology, 0.08% and 0.11% for ASCUS, and 0.04% and 0.07% for LSIL, respectively. Stratifying risk by biopsy result at initial colposcopy, 3- and 5-year CIN3 incidences were 2.85% and 3.81% with a negative biopsy, 7.09% and 8.32% with an LSIL biopsy, and 4.11% and 5.2% when no biopsy was done, respectively. Three- and 5-year incidence of invasive cancer was 0% and 0.05% after a negative biopsy, 0% and 0% after LSIL biopsy, and 0.05% and 0.08% when no biopsy was done, respectively.When initial colposcopy is done after a low-grade screening cytology result andlt;CIN2 is identified, the risk of CIN3 and invasive cancer is low, particularly when biopsies indicate LSIL. Surveillance strategies should balance the likelihood of detecting CIN3 with the potential harms over management with too frequent screening or colposcopic interventions in low-risk patients.

Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA) or liquid biopsy. Here, we analyze if cell-free human papillomavirus DNA (ctHPV DNA) is detectable before, during and after treatment, in patients with cervical cancer or pre-malignant lesions that may develop into cervical cancer, and whether ctHPV DNA levels were correlated to patient or tumor characteristics and outcome. Furthermore, total cell-free DNA load is studied using cfAlbumin DNA as a surrogate marker.18 patients with locally advanced CC (LACC), 15 patients with early stage CC (ESCC) and 21 patients with pre-malignant lesions, all with verified HPV16, 18 or 45-positive lesions, were included. Pre- during- and post-treatment plasma were tested for HPV16, 1845 and total cfDNA load using droplet digital PCR.ctHPV DNA was found in 94.4% and 26.7% of pre-treatment plasma of patients with LACC and ESCC respectively, while all samples from patients with pre-malignant lesions were negative. Higher levels of ctHPV DNA were correlated to higher FIGO2018 stage. Patients with LACC and persistent ctHPV DNA at end-of-treatment had significantly worse progression-free survival (PFS) than patients who had cleared the ctHPV DNA (p = 0.007). Patients with total ctDNA-levels above median in pre-treatment plasma had a worse PFS (p = 0.026), compared to patients with total ctDNA-levels below median.ctHPV DNA is a promising prognostic biomarker in locally advanced cervical cancer that should be studied further for clinical use.

Aims of this study are assessing prevalence of anal human papillomavirus (HPV) genotypes in male who have sex with men (MSM) living with HIV over a period of 5 years and determining risk factors for anal infection from high-risk (HR) HPV genotypes or included in vaccine Gardasil 9.Time-trend, monocentric study on MSM living with HIV who underwent HPV test at anal site from 2015 to 2019.Anal swabs were processed by multiplex real-time polymerase chain reaction to detect HPV genotypes. The Cochran-Armitage test was used to assess linear trend in HPV prevalence over time and logistic regression models to estimate risk factors.Of the 1352 MSM living with HIV, 168 (12%) were not infected by any HPV genotypes and only 6 were infected with a maximum of 6 genotypes; prevalence of HR-HPV genotypes or those included in the 9-valent vaccine remained stable over time. At multivariable analysis, the risk of carrying at least 1 genotype classified as HR or included in Gardasil 9 was associated with younger age [adjusted odds ratio (aOR) for younger than 30 years vs older than 45 years (95% confidence interval) 2.714 (1.484 to 4.961), P = 0.001, and 1.868 (1.141 to 3.060), P0.013, respectively] and a history of gonorrhea [aOR 2.118 (1.100 to 4.078), P = 0.025, and 1.785 (1.056 to 3.018), P = 0.031, respectively].Our findings suggest that prevalence remained stable over time and that all MSM with HIV would benefit from Gardasil 9 immunization, particularly the youngest and those with a prior gonococcal infection.

Persistent infection of high-risk human papillomavirus (HPV) is a leading cause of some cancers, including cervical cancer. However, with over 20 carcinogenic HPV types, it is difficult to design a multivalent vaccine that can offer complete protection. Here, we describe the design and optimization of a HPV51/69/26 triple-type chimeric virus-like particle (VLP) for vaccine development. Using E. coli and a serial N-terminal truncation strategy, we created double- and triple-type chimeric VLPs through loop-swapping at equivalent surface loops. The lead candidate, H69-51BC-26FG, conferred similar particulate properties as that of its parental VLPs and comparable immunogenicity against HPV51, -69 and -26. When produced in a GMP-like facility, these H69-51BC-26FG VLPs were verified to have excellent qualities for the development of a multivalent HPV vaccine. This study showcases an amenable way to create a single VLP using type-specific epitope clustering for the design of a triple-type vaccine.

Patients with human papillomavirus oropharyngeal cancer are highly curable but risk significant long-term toxic effects with standard therapy. This study investigated a de-escalation strategy of decreased adjuvant radiation therapy and chemotherapy after transoral robotic surgery, and reports on long-term functional and quality of life (QOL) outcomes.Eligible patients had a p16-positive oropharyngeal cancer and ≤10 pack-year smoking history and underwent surgery followed by treatment with either 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks with weekly docetaxel (15 mg/mSeventy-nine patients (89.9% male) were treated and eligible for toxic effect and functional evaluation. Dry mouth was the most common grade 1 toxic effect at 1 year (55.6%), 2 years (53.3%), and 3 years (49.2%). The cumulative rates of grade 2 toxic effects at 1, 2, and 3 years were 1.4%, 6.7%, and 6.8%, respectively. There were only 2 grade 3 toxic effects at ≥1 year, including a grade 3 fatigue at 2.5 years, and a grade 3 superficial soft tissue fibrosis at 4 years. There were no grade 4 to 5 toxic effects. No patients were percutaneous endoscopic gastrostomy-dependent. Swallow function improved by 12 months posttreatment. QOL improved over time by all measurement tools and most patients returned to baseline level of function and QOL.De-escalated adjuvant therapy for select patients with human papillomavirus oropharyngeal cancer resulted in low rates of long-term toxic effects, excellent swallow outcomes, and preservation of global and xerostomia-related QOL.

Women living with HIV (WLWH) have increased risk of human papillomavirus (HPV) infection, precancers, and invasive cervical cancers. This study aims to determine the rate of cervical cytologic progression and related factors in minority WLWH across 5 years.We used our HIV clinic database, complemented with a retrospective chart review to identify WLWH with a baseline negative cervical cytology between 2009 and 2012 and 5-year follow-up. Data included race/ethnicity, age, years living with HIV, AIDS status, viral load, history of smoking, drug use, and HPV status. Multivariate logistic regression tested progression of negative cytology to low-grade/high-grade squamous intraepithelial lesions (LGSIL/HGSIL).Among 162 WLWH, 42% were African American, 30% non-Hispanic African Caribbean, and 26% Hispanic. At baseline, 21% had detectable viral load (200 cp/mL), mean age was 44.8 (±11 years), and mean years living with HIV was 9.6 (±6.9). After 5 years, 19% of the cohort progressed to LGSIL/HGSIL. Human papillomavirus was detected consistently among women with cytologic changes (30% vs 7%, p.01). Significant factors that predicted higher likelihood of progression to LGSIL/HGSIL were detection of HPV (adjusted odds ratios = 5.11 [1.31-19.93]; p = .02), and Centers for Disease Control and Prevention-defined AIDS status (adjusted odds ratios = 4.28 [1.04-17.63]; p = .04). Of the women who maintained negative cytology at 1 to 2 years (n = 102), 5 women (5%) progressed during the following 3 years before the recommended follow-up.Human papillomavirus detection and AIDS status were significant factors predicting progression to LGSIL/HGSIL among minority WLWH. Providers screening WLWH for cervical intraepithelial neoplasia should carefully decide screening intervals for minority populations.

Human papillomavirus (HPV) is an important public health concern due to its causative role in many cancers, especially cervical cancer, and other conditions that lead to serious health consequences in both men and women. In Latin America and the Caribbean, nearly 60,000 new cases of cervical cancer and another 7,000 HPV-associated cancers are diagnosed annually.HPV vaccination combined with comprehensive cervical cancer control programmingis paving the way for eliminating cervical cancer as a major public health problem and drastically reducing other HPV-associated diseases. To date, 44 countries and territories in the Americas have introduced HPV vaccines as part of their national immunization programs and cervical cancer control strategies. Early lessons from HPV vaccine introduction suggest that transparent and credible evidence-based decision-making, information, education and communication about HPV and cervical cancer, coordination with existing cervical cancer control initiatives, and precise planning for ensuring effective uptake of the vaccine in target groups are all critical elements of success.There is an urgent need for strategies to increase HPV vaccine coverage, and as the integrated control programs evolve and other HPV-associated disease becomes important for public health, there will be a need for continued program and policy evaluation.

Objectives Data on Papanicolaou (Pap) tests with atypical glandular cells (AGCs) with concurrent squamous cell abnormalities (AGC + Sq) are limited. We evaluated histologic outcomes and the role of high-risk human papillomavirus (HR-HPV) testing in this setting compared with AGCs without concurrent squamous cell abnormalities (AGC-alone). Methods This study used a retrospective cohort of patients with Pap test diagnoses of AGC + Sq and AGC-alone between October 2013 and August 2021. Results We included 287 Pap tests from 278 patients. The HR-HPV test was positive in 55% of AGC + Sq cases and 14% of AGC-alone cases (P < .0001). Most AGC + Sq cases displayed squamous lesions (41.5%) or were benign (41.5%) on histology, whereas AGC-alone cases were predominantly benign (72%) or extracervical neoplasms (18%). AGC + Sq cases showed higher rates of significant histologic lesions (P = .0001), which were associated with positive HR-HPV status (P = .0012). In AGC-alone cases, HR-HPV status was associated with significant histology only in patients 50 years of age or younger. In both groups, 20% or more of HR-HPV–negative patients harbored significant lesions. Conclusions AGC + Sq represents a distinct group of patients. HR-HPV testing and patient age provide useful information in the evaluation of AGC, but triage based on HR-HPV testing is not recommended because of the potential for missing significant lesions.

Oncogenic human papillomavirus (HPV) types control the phenotype of cervical cancer cells through the sustained expression of the viral E6/E7 oncogenes. Here, we show that they strongly restrain expression of the putative tumor suppressor protein Dkk1 (Dickkopf-1) in HPV-positive cervical cancer cells through the restriction of p53 expression by the continuously expressed endogenous E6 oncoprotein. Moreover, our study reveals that compromised Dkk1 expression is linked to increased resistance of HPV-positive cervical cancer cells toward the proapoptotic activity of Cisplatin. Although Dkk1 can act as a Wnt antagonist, the antiapoptotic effect resulting from Dkk1 repression is not linked to an activation of this pathway. Rather, transcriptome and functional analyses uncover that Dkk1 repression leads to a strongly diminished stimulation of c-Jun N-terminal kinase (JNK) signaling which is required for efficient apoptosis induction by Cisplatin in cervical cancer cells. Further, we observed that Dkk1-depleted cervical cancer cells induce senescence under Cisplatin treatment instead of apoptosis, suggesting that Dkk1 levels can strongly influence the phenotypic response of these cells toward Cisplatin. Collectively, these results provide new insights into the virus/host cell crosstalk in cervical cancer cells by identifying Dkk1 as a cellular target which is maintained under strong negative control by the continuous expression of the HPV oncogenes. Moreover, they identify Dkk1 as a critical determinant for the sensitivity of cervical cancer cells toward Cisplatin, showing that Dkk1 repression leads to increased Cisplatin resistance by impairing proapoptotic JNK signaling.

Human papillomavirus (HPV) testing using self-collected vaginal samples and urine samples is convenient and effective for improving the screening rate. But, to serve as an alternative cervical cancer screening technique, such tests must offer sensitivity equivalent to the HPV testing of physician-collected cervical samples. To examine the effectiveness of HPV testing using self-collected samples and urine samples, we compared the results of HPV testing using these samples with those of HPV testing using physician-collected samples and cytological examinations.The study population included 300 women (age: 20-50 years) with abnormal cervical cytology. The results of HPV testing using self-collected samples and urine samples and physician-collected samples and cervical cytology were compared.For all HPV types, the κ-value was 0.773 for physician- and self-collected samples and 0.575 for physician-collected and urine samples. The κ-value for HPV type 16-positive samples was 0.988 for physician- and self-collected samples and 0.896 for physician-collected and urine samples. The κ-value for HPV type 18-positive samples was 0.856 for physician- and self-collected samples and 0.831 for physician-collected and urine samples. For other HPV types, the value was 0.809 for physician- and self-collected samples and 0.617 for physician-collected and urine samples.The obtained results were consistent between physician- and self-collected samples as well as between physician-collected and urine samples. Considering that the agreement rate was particularly high for the high-risk HPV types 16 and 18, HPV testing using physician-collected samples, self-collected samples, and urine samples was equally effective for the types with high carcinogenicity.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major issue involves validating more HPV tests. In recent years, some HPV tests are used for clinical performance verification in China. The purpose of this study was to explore whether the BD Onclarity (Becton, Dickinson and Company)HPV assay differs from the Roche cobas (Roche Molecular Systems)HPV assay, as determined using 944 cervical samples, including 588 with sequencing results. In the nucleic acid assay accuracy verification, the assays showed excellent concordance for detection of HPV16 (κ = 0.93, 95% confidence interval [CI]: 0.89-0.97) and HPV18 (κ = 0.90, 95% CI: 0.83-0.97), and very good concordance for the 12 other high-risk types (HPV31/33/35/39/45/51/52/56/58/59/66/68, κ = 0.79, 95% CI: 0.75-0.83). The overall agreement for HPV DNA detection between Onclarity and cobas was very good (κ = 0.7755). No difference for ≥CIN2 sensitivity was observed between Onclarity and cobas (both 96.5%), whereas the ≥CIN2 specificity for detection of Onclarity (16.6%, 95% CI: 13.7-19.9) was higher than that of cobas (11.5%, 95% CI: 9.1-14.5). Onclarity exhibited comparable screening performance and triage efficiency compared to cobas in the detection of cervical disease in Chinese women.

Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (high-risk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20 mo; mean, 9 mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPV-independent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.

Introduction. High carcinogenic-risk human papillomaviruses (hrHPVs) are recognized as etiological agents of cervical cancer. Constant expression of the viral oncoproteins, E6 and E7, is required for maintenance of the malignant phenotype of tumor cells. The exact mechanism of regulation of viral oncogenes expression in tumor cells is not fully elucidated. The purpose: identification of viral noncoding RNAs (ncRNAs) in HPV16-positve cervical cancer. Materials and methods. The reverse transcription polymerase chain reactions were used to detect viral ncRNAs in HPV16-positve primary cervical squamous cell carcinomas and SiHa and CasKi cell lines. The knockdown technique with oligonucleotides complementary to ncRNAs was used to elucidate their functions. Results. We have identified ncRNAs transcribed in the upstream regulatory region of HPV16 in the cervical carcinoma cell lines and in 32 out 32 cervical squamous cell carcinomas with episomal or integrated forms of HPV16 DNA. Knockdown of sense or antisense strains of ncRNAs by oligonucleotides results in a decrease or increase of the E6 and E7 oncogenes mRNA levels in cells, respectively. These changes of oncogenes mRNA levels are accompanied by the modulation of the levels of the p53 protein, the main target of the E6 oncoprotein. Conclusion. The presence of regulatory ncRNAs in all examined tumors and cell lines revealed for the first time indicates their necessity for maintenance of constant expression of E6 and E7 oncogenes in them. The findings can be useful for understanding of the fundamental aspects of the viral expression regulation in HPV16-positive tumors.

The intratumor heterogeneity of human papillomavirus (HPV)-related cervical cancer remains poorly defined. We performed single-cell RNA sequencing on 18 046 individual cells derived from two HPV-related cervical adenosquamous carcinoma samples to analyze the transcriptional heterogeneity of both epithelial and immune constituents, identifying seven epithelial (Epi1-7) and 11 immune subclusters. Based on expression of known cervical cancer markers, Epi1-2 primarily displayed features of adenocarcinoma, whereas Epi3-6 were instead characterized by features of squamous carcinoma. Our analyses also revealed that hypoxia and Kirsten rat sarcoma viral oncogene signaling were highly represented within Epi1; metabolic pathways mediating glycolysis and oxidative phosphorylation were enriched in Epi2-4; while Epi5 was enriched in p53 pathway components and features of epithelial-mesenchymal transition. Moreover, CD8

Cutaneous warts caused by human papillomavirus are benign proliferative lesions that occur at any ages in human lives. Updated, comprehensive and systematic evidence-based guidelines to guide clinical practice are urgently needed.We collaborated with multidisciplinary experts to formulate this guideline based on evidences of already published literature, focusing on 13 clinical questions elected by a panel of experts. We adopted Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to form classification of recommendations as well as the improved Delphi method to retain respective recommendations with a consensus degree of over 80%.Our guideline covered aspects of the diagnosis and treatment of cutaneous warts such as diagnostic gold standard, transmission routes, laboratory tests, treatment principle, clinical cure criterion, definitions, and treatments of common warts, flat warts, plantar warts, condyloma acuminatum, and epidermodysplasia verruciformis. Recommendations about special population such as children and pregnant women are also listed. In total, 49 recommendations have been obtained.It is a comprehensive and systematic evidence-based guideline and we hope this guideline could systematically and effectively guide the clinical practice of cutaneous warts and improve the overall levels of medical services.

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result ingt;62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.

Cervical cancer is the fourth cancer in incidence and the third in mortality among women worldwide. Women living with HIV have a significantly increased risk of cervical cancer. The immune response of the host is crucial to determine the course of the human papillomavirus (HPV) infection and cytokines play an important role modulating viral multiplication and concentrating the immune response in the Th1 or Th2 pattern. The aim of this study is to evaluate the available evidence on the concentration of genital cytokines and their role in HPV infection in HIV-infected women. A systematic search of the literature was performed using MEDLINE by PubMed, Embase, Cochrane, LILACS, Scopus, Science direct, and Web of Science databases on November, 2020, in which the following clusters of terms were applied: HIV infection, HPV infection, and cytokine. Initially, 728 articles were selected, but only 17 were eligible for full-text review, and among them, 9 were included in the qualitative analysis. No restriction was applied in language, publication date, or status. The most studied cytokines in the articles included in this review were interferon (IFN)-γ and interleukin (IL)-10 (six articles), tumor necrosis factor (TNF) and IL-6 (five articles), and macrophage inflammatory protein (four articles). The main findings show that there is a reduction in the number of cells expressing IFN-γ (

WHO recommends human papillomavirus (HPV) testing and same-day treatment for cervical screening in low-income and middle-income countries (LMICs); however, few published data exist on the validity of the strategy. We aimed to evaluate the clinical performance, treatment completion rates, adverse events profile, and acceptability of a fully integrated strategy, comprising point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation, for screening of cervical cancer in women in Papua New Guinea.HPV-STAT was a large-scale, prospective, single-arm intervention trial conducted at two clinical sites in Papua New Guinea. Cervical screening clinics with an on-site consultant gynaecologist were selected in consultation with national and provincial health authorities, church health services, and local stakeholders. Eligible participants were women aged 30-59 years attending cervical screening services at the two clinics, who were willing to comply with study procedures and able to provide written informed consent. Women self-collected vaginal specimens for point-of-care GeneXpert testing (Cepheid, Sunnyvale, CA, USA) for oncogenic HPV types. Women testing positive for HPV underwent pelvic examination followed by same-day thermal ablation or referral for gynaecology review. All HPV-positive women and a 15% random sample of HPV-negative women provided a clinician-collected cervical specimen for liquid-based cytology. The primary outcome was clinical performance (ie, sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the strategy for the detection of high-grade squamous intraepithelial lesion (HSIL) or worse. This trial is registered with ISRCTN, ISRCTN13476702.Between June 5, 2018, and Jan 6, 2020, we recruited 4285 women, 3638 (84·9%) of whom tested negative for HPV and 647 (15·1%) tested positive for one or more oncogenic HPV type. Sensitivity of the algorithm to detect HSIL or worse was 85·4% (95% CI 81·0-89·6), with specificity 89·6% (88·6-90·6), PPV 35·2% (31·6-39·0), and NPV 98·9% (98·6-99·2). Among HPV-positive women, 602 (93·0%) received same-day thermal ablation and 42 (6·5%) were referred for gynaecology review, 37 (88·1%) of whom attended. Acceptability was high among both HPV-positive and HPV-negative women. Among the 329 HPV-positive women who attended a 3-month follow-up visit, 51 (15·5%) reported mild adverse symptoms that resolved in all cases by the follow-up visit. There were no serious adverse events.We conducted the first real-world evaluation of a fully integrated point-of-care HPV self-collect, test, and treat strategy for same-day cervical screening in a LMIC and found it to be effective, acceptable, and safe when implemented at scale in primary health-care facilities in Papua New Guinea. Our findings support the introduction and scale-up of HPV screening and treatment for the control and elimination of cervical cancer in LMICs, as recommended by WHO.Australian National Health and Medical Research Council.

This study reviewed the literature to assess the available evidence for the ability of biomarkers based on human papillomavirus (HPV) methylation (i.e., the detection of methyl groups in HPV DNA in cervical specimens) to screen for cervical precancerous and cancerous lesions. Scientific databases were searched, and abstracts screened for relevance. The quality of the included articles was assessed using a quality assessment tool called QUADAS-2. The main diagnostic performance parameter extracted from the included articles was the receiver operating characteristic (ROC), a measure of the ability of a biomarker to detect all true cases (true positives) while excluding all true non-cases (true negatives). After screening, nine articles were included, of which seven were of moderate quality and two were of high quality. ROC data were extracted for 27 biomarkers, of which four methylation biomarkers had high diagnostic ability (i.e., ROC 0.900), 17 had moderate diagnostic ability (ROC: 0.7000–0.8999) and six had low diagnostic ability (ROC 0.700). An umbrella meta-analysis (i.e., a weighted-average ROC for all HPV methylation biomarkers) revealed an ROC consistent with moderate diagnostic ability (0.770). The main conclusion from this study was that HPV methylation biomarkers, especially ones with high diagnostic ability, hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

National HPV vaccination coverage in Japan is less than one percent of the eligible population and cervical cancer incidence and mortality are increasing. This systematic review and meta-analysis aimed to provide a comprehensive estimate of HPV genotype prevalence for Japan.English and Japanese databases were searched to March 2021 for research reporting HPV genotypes in cytology and histology samples from Japanese women. Summary estimates were calculated by disease stage from cytology only assessment - Normal, ASCUS, LSIL, HSIL and from histological assessment - CIN1, CIN2, CIN3/AIS, ICC (ICC-SCC, and ICC-ADC), and other. A random-effects meta-analysis was used to calculate summary prevalence estimates of any-HPV, high-risk (HR) and low-risk (LR) vaccine types, and vaccine genotypes (bivalent, quadrivalent, or nonavalent). This study was registered with PROSPERO: CRD42018117596.A total of 57759 women with normal cytology, 1766 ASCUS, 3764 LSIL, 2017 HSIL, 3130 CIN1, 1219 CIN2, 869 CIN3/AIS, and 4306 ICC (which included 1032 ICC-SCC, and 638 ICC-ADC) were tested for HPV. The summary estimate of any-HPV genotype in women with normal cytology was 15·6% (95% CI: 12·3-19·4) and in invasive cervical cancer (ICC) was 85·6% (80·7-89·8). The prevalence of HR-HPV was 86·0% (95% CI: 73·9-94·9) for cytological cases of HSIL, 76·9% (52·1-94·7) for histological cases of CIN3/AIS, and 75·7% (68·0-82·6) for ICC. In women with ICC, the summary prevalence of bivalent vaccine genotypes was 58·5% (95% CI: 52·1-64·9), for quadrivalent genotypes was 58·6% (52·2-64·9) and for nonavalent genotypes was 71·5% (64·9-77·6), and of ICC cases that were HPV positive over 90% of infections are nonavalent vaccine preventable. There was considerable heterogeneity in all HPV summary estimates and for ICC, this heterogeneity was not explained by variability in study design, sample type, HPV assay type, or HPV DNA detection method, although studies published in the 1990s had lower prevalence estimates of any-HPV and HR HPV genotypes.HPV prevalence is high among Japanese women. The nonavalent vaccine is likely to have the greatest impact on reducing cervical cancer incidence and mortality in Japan.

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is increasing in incidence and is often first diagnosed on a cytology fine needle aspiration (FNA) specimen of metastatic nodal disease of the neck. In the setting of oropharyngeal squamous cell carcinoma, HPV status defines the disease with HPV-associated tumors having better overall prognosis than those that are HPV negative. Furthermore, metastatic squamous cell carcinoma of the neck of unknown origin requires testing for HPV as a positive result suggests an oropharyngeal primary. As a result, HPV testing in aspirate samples is increasingly important for the proper diagnosis and treatment of patients with head and neck squamous cell carcinoma. Although HPV testing in cervicovaginal cytology specimens is common and well-established, testing in head and neck FNA samples remains challenging. p16 immunohistochemistry is an excellent surrogate marker for HPV in tumors of known or suspected oropharyngeal origin, but the criteria used in histologic specimens may not be appropriate in cytology samples. FNA samples are more frequently hypocellular, and cytology cell blocks have variable fixation and processing steps, limiting the utility of p16 immunohistochemistry. Other potential testing options have been reported in the literature including staining of aspirate smears and molecular testing of liquid-based samples. The American Society of Cytopathology Clinical Practice Committee recently surveyed the American Society of Cytopathology membership to determine the current state of HPV testing in aspirate samples, and this review article is designed to provide a summary of the current literature on various testing options in FNA samples.

Preclinical data support investigation of selective CDK4/6 inhibition as a therapeutic strategy for human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC). Phase 1 clinical trials established the feasibility of combining palbociclib with cetuximab in patients with recurrent or metastatic HNSCC. Nonrandomized phase II trials showed that palbociclib plus cetuximab resulted in efficacy outcomes better than cetuximab in biomarker-unselected, platinum-resistant or cetuximab-resistant, HPV-unrelated HNSCC. A double-blind, randomized phase II trial (PALATINUS) evaluated the efficacy of palbociclib or placebo and cetuximab in patients with biomarker-unselected, platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC. Palbociclib and cetuximab did not significantly prolong overall survival compared with placebo and cetuximab. However, correlative biomarker analyses identified that trends for better overall survival with palbociclib and cetuximab were observed in certain prespecified subsets; the largest reduction in risk of death with palbociclib versus placebo and cetuximab occurred in the subset with CDKN2A mutations. Several phase II-III trials are underway investigating palbociclib in biomarker-selected patients with HPV-unrelated locally advanced or recurrent or metastatic HNSCC.

Persistent human papillomavirus (HPV) infection is responsible for the majority of oropharyngeal and cervical cancers in the USA. Currently, HPV curricula within medical and dental schools are not standardized. As such, we implemented a brief online educational intervention to increase medical and dental trainees' knowledge of the HPV vaccine and the association between HPV and cancer. The objectives of this study were to (1) assess medical and dental trainees' baseline knowledge regarding HPV and HPV vaccine, (2) determine the willingness to recommend the HPV vaccine to patients, and (3) evaluate the impact of an online intervention on HPV-related knowledge. Medical and dental trainees from two large academic centers in the USA were asked to fill out an online pre-intervention questionnaire, followed by a 10-min HPV educational intervention based on the Center of Disease Control and Prevention (CDC) resources, and then a post-intervention questionnaire. There were 75 participants (67.4% females; median age 18-30years). When asked about HPV-related cancer types, the correct response increased from 28.4% (pre-intervention) to 51.9% (post-intervention; p

The updated 2020 World Health Organization (WHO) classification divides endocervical adenocarcinomas (EACs) into human papillomavirus-associated (HPVA) and -independent (HPVI) tumors. The purpose of this study was to review our EAC cases and re-classify them according to the updated WHO classification.We reviewed the hematoxylin and eosin-stained slides of 123 EACs and reclassified them according to the updated WHO classification.Eighty-one (65.9%) and 42 (34.1%) patients had HPVA and HPVI EACs, respectively. The usual (60/81; 74.1%) and gastric (31/42; 73.8%) types were the most common HPVA and HPVI EACs, respectively. Signet-ring cell (1/123; 0.8%), invasive stratified mucin-producing (10/123; 8.1%), clear-cell (4/123; 3.3%), mesonephric (3/123; 2.4%), and serous (1/123; 0.8%) types were uncommon. Unusual morphologies were seen, including microcystic, elongated, and fragmented patterns of stromal invasion, micropapillary growth patterns, and gastric-type adenocarcinoma in situ.We successfully reclassified all the examined cases based on morphology alone. The numbers and relative proportions of EAC histotypes were variable. We found some uncommon histotypes, as well as unusual but clinically important histological features.

The aim of this paper is to model the dynamics of the human papillomavirus (HPV) in cervical epithelial cells. We developed a mathematical model of the epithelial cellular dynamics of the stratified epithelium of three (basale, intermedium, and corneum) stratums that is based on three ordinary differential equations. We determine the biological condition for the existence of the epithelial cell homeostasis equilibrium, and we obtain the necessary and sufficient conditions for its global stability using the method of Lyapunov functions and a theorem on limiting systems. We have also developed a mathematical model based on seven ordinary differential equations that describes the dynamics of HPV infection. We calculated the basic reproductive number ( R 0 ) of the infection using the next-generation operator method. We determine the existence and the local stability of the equilibrium point of the cellular homeostasis of the epithelium. We then give a sufficient condition for the global asymptotic stability of the epithelial cell homeostasis equilibrium using the Lyapunov function method. We proved that this equilibrium point is nonhyperbolic when R 0 = 1 and that in this case, the system presents a forward bifurcation, which shows the existence of an infected equilibrium point when R 0 > 1 . We also study the solutions numerically (i.e., viral kinetic in silico) when R 0 > 1 . Finally, local sensitivity index was calculated to assess the influence of different parameters on basic reproductive number. Our model reproduces the transient, acute, latent, and chronic infections that have been reported in studies of the natural history of HPV.

The recurrence rate of head and neck squamous cell carcinoma (HNSCC) remains high; thus the control of recurrence is a clinical problem to be challenged. To clarify the precise mechanism, specific immunological biomarkers responsible for recurrence were investigated.The expression levels of immune response-associated and Shizuoka Cancer Center 820 cancer-associated genes, and genetic mutations from whole-exome sequencing were compared between HNSCC patients who developed recurrence (n=8) and HNSCC patients who did not develop recurrence (n=19) using a volcano plot analysis. Cytokine and epithelial-mesenchymal transition marker genes were analyzed using quantitative PCR. Tumor-infiltrating lymphocytes, immune checkpoint molecules, and human papilloma virus status were investigated using immunohistochemistry (IHC).Twenty-seven evaluable patients with HNSCCs received radiation therapy after surgery. Recurrence was identified in 8 patients. TP53 mutations tended to be higher in patients who developed recurrence than in those who did not develop recurrence (75% vs. 31.6%). Gene expression profiling showed the down-regulation of T cell activation genes (ICOS, CD69 and CD83) and the upregulation of the ERBB4, EGFR, VEGF, HIF1A, TGFB1, TWIST1, IL-8, and PAX7 genes, which suggested the activation of the TP53 mutation-TGF-β1-PAX7 pathway and epithelial-mesenchymal transition. Additionally, IHC indicated a tendency toward a reduction in T cell accumulation and an increase in M2-type macrophage infiltration in tumors that recurred.A TP53 mutation-mediated immune-suppressive state in the tumor microenvironment and TGF-β1-PAX7-mediated EMT might contribute to the promotion of recurrence in patients with HNSCC after postoperative radiotherapy.

Objectives To describe risk factors/incidence of abnormal cervical/vaginal cytology/histology and cancer among women living with human immunodeficiency virus (WLHIV) ≥65 years compared to HIV-negative matched controls Study Design Retrospective cohort of patients who underwent Pap screening at the University of Maryland 01/2003-04/2019. Results WLHIV and HIV-negative controls ( n = 70 each) underwent 140/151 Pap tests, respectively. Among WLHIV, 29% exhibited abnormal results and were less likely than HIV-negative women with normal Paps to have had serially negative Pap tests prior to age 65 ( p = .03). In both groups, 1.4% developed cervical cancer. Abnormal Paps were more frequent in WLHIV than in HIV-negative women (31% vs 10%, p < .0001, RR:3.2, 95%CI1.9–5.4) as was HRHPV (high-risk human papillomavirus) status (43% vs 19%, p = .0233, RR:2.3, 95%CI1.2–4.6). The RR for an abnormal Pap was 2.6 (95% CI:1.1–4.2) for VL >1000 copies/mL and 0.4 (95% CI:0.2–0.7) for CD4 count of >200 cells/μL. No individual with an initially normal Pap experienced an abnormal result over a mean of 42.5 and 43.5 months in the HIV-positive and HIV-negative groups, respectively. Conclusions HIV status was associated with a higher rate of abnormal Pap/HRHPV; however, no significant difference in cervical/vaginal cancer. Elevated VL/low CD4 count were associated with greater risk for an abnormal Pap.